Type

Journal Article

Authors

Ann M Hopkins
Yvonne E Smith
Arnold D K Hill
Leonie S Young
Elaine W Kay
Katherine M Sheehan
Bassam Abdulkarim
Siham Sabri
Norma O'Donovan
Lance Hudson
and 5 others

Subjects

Biochemistry

Topics
cancer cells drug resistant cells protein expression human epidermal growth factor receptor 2 anti cancer cell lines breast cancer junctional adhesion molecule a

Cleavage of the extracellular domain of junctional adhesion molecule-A is associated with resistance to anti-HER2 therapies in breast cancer settings. (2017)

Abstract Junctional adhesion molecule-A (JAM-A) is an adhesion molecule whose overexpression on breast tumor tissue has been associated with aggressive cancer phenotypes, including human epidermal growth factor receptor-2 (HER2)-positive disease. Since JAM-A has been described to regulate HER2 expression in breast cancer cells, we hypothesized that JAM-dependent stabilization of HER2 could participate in resistance to HER2-targeted therapies. Using breast cancer cell line models resistant to anti-HER2 drugs, we investigated JAM-A expression and the effect of JAM-A silencing on biochemical/functional parameters. We also tested whether altered JAM-A expression/processing underpinned differences between drug-sensitive and -resistant cells and acted as a biomarker of patients who developed resistance to HER2-targeted therapies. Silencing JAM-A enhanced the anti-proliferative effects of anti-HER2 treatments in trastuzumab- and lapatinib-resistant breast cancer cells and further reduced HER2 protein expression and Akt phosphorylation in drug-treated cells. Increased epidermal growth factor receptor expression observed in drug-resistant models was normalized upon JAM-A silencing. JAM-A was highly expressed in all of a small cohort of HER2-positive patients whose disease recurred following anti-HER2 therapy. High JAM-A expression also correlated with metastatic disease at the time of diagnosis in another patient cohort resistant to trastuzumab therapy. Importantly, cleavage of JAM-A was increased in drug-resistant cell lines in conjunction with increased expression of ADAM-10 and -17 metalloproteases. Pharmacological inhibition or genetic silencing studies suggested a particular role for ADAM-10 in reducing JAM-A cleavage and partially re-sensitizing drug-resistant cells to the anti-proliferative effects of HER2-targeted drugs. Functionally, recombinant cleaved JAM-A enhanced breast cancer cell invasion in vitro and both invasion and proliferation in a semi-in vivo model. Finally, cleaved JAM-A was detectable in the serum of a small cohort of HER2-positive patients and correlated significantly with resistance to HER2-targeted therapy. Collectively, our data suggest a novel model whereby increased expression and cleavage of JAM-A drive tumorigenic behavior and act as a biomarker and potential therapeutic target for resistance to HER2-targeted therapies.
Collections Ireland -> Dublin City University -> PubMed

Full list of authors on original publication

Ann M Hopkins, Yvonne E Smith, Arnold D K Hill, Leonie S Young, Elaine W Kay, Katherine M Sheehan, Bassam Abdulkarim, Siham Sabri, Norma O'Donovan, Lance Hudson and 5 others

Experts in our system

1
Ann M Hopkins
Royal College of Surgeons in Ireland
Total Publications: 26
 
2
Yvonne E Smith
Royal College of Surgeons in Ireland
Total Publications: 6
 
3
Arnold D K Hill
Royal College of Surgeons in Ireland
Total Publications: 110
 
4
Leonie S Young
Royal College of Surgeons in Ireland
Total Publications: 42
 
5
Elaine W Kay
Royal College of Surgeons in Ireland
Total Publications: 157
 
6
K M Sheehan
Dublin City University
Total Publications: 14
 
7
Norma O'Donovan
Dublin City University
Total Publications: 59
 
8
Lance Hudson
Royal College of Surgeons in Ireland
Total Publications: 11